Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease

Eur J Pharmacol. 2023 Mar 5:942:175521. doi: 10.1016/j.ejphar.2023.175521. Epub 2023 Jan 19.


Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.

Keywords: Albuminuria; Diabetic kidney disease; Glycosuria; Megalin; Proximal tubule; Sodium glucose co-transporter.

MeSH terms

  • Albumins / metabolism
  • Albuminuria
  • Animals
  • Diabetes Mellitus, Experimental* / chemically induced
  • Diabetes Mellitus, Experimental* / complications
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetic Nephropathies* / metabolism
  • Glucose / adverse effects
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Proteins / metabolism
  • Rats
  • Sodium-Glucose Transporter 2 / metabolism


  • dapagliflozin
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Sodium-Glucose Transporter 2
  • Proteins
  • Albumins
  • Glucose